Telomeres are unique terminal chromosomal structures that shorten with cell division in vitro and with increased age in vivo for human somatic cells. Telomerase, a ribonucleoprotein enzyme that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells and is absent in most normal human somatic cells. However, we demonstrated that telomerase is in fect highly regulated during development and activation of mouse and human lymphocytes. Expression of the two genes encoding the necessary and sufficient components of telomerase, RNA template (TR) and reverse transcriptase catalytic component (TERT), was found to be regulated during lymphocyte development and activation. Our studies of genetically engineerd knockout mice have demonstrated that, in addition to the defect in telomere length maintenance observed in complete homozygous knockouts for either of the telomerase components, there is a deficiency in telomere maintenance in mice that are heterozygous for inactivation of one copy of either telomerase component. This phenomenon, termed haplo-insufficiency, has recently been observed in an increasing number of clinical entities, including dyskeratosis congenita, aplastic anemia, and pulmonary fibrosis, resulting from mutation and inactivation of telomerase components or related genes. In collaboration with the laboratory of Dr. Neal Young (NHLBI), we have assessed the impact of parental haplo-insufficiency for telomere maintenance on the telomere length and function of genetically normal or abnormal offspring in these affected families. The outcome of studies in mice and humans demonstrated that inheritance of telomere length is not determined by species-specific homeostatic mechanisms, but appears to be determined largely by stochastic factors. Cell survival and proliferation are also regulated by the p53 tumor suppressor molecule. Although the function of p53 in preventing malignant transformation and tumorigenesis is well established, there is much less understanding of the role of p53 in normal cell function. Ataxia-telangiectasia mutated (ATM) is a kinase that plays a central role in maintaining genomic integrity. In both humans and mice, ATM deficiency is associated with an increased incidence of lymphoid cancers that are primarily T cell in origin. We asked if ATM plays a more general role in preventing non-T cell malignancies by breeding mice that were both ATM- and T cell-deficient. This model removes T cells as targets for lymphomagenesis as well as eliminating T cell-dependent immune surveillance. These mice exclusively develop early onset IgM+ B cell lymphomas that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B cell lymphomas (DLBCL). Tumors express clonal as well as emerging IghV hypermutation, and express AID, but B lymphoma development is independent of AID, occurring at equal frequency in AID knockout mice. Lymphomas express high levels of MHCII and costimulatory molecules, are highly stimulatory to T cells in vitro, and grow in vivo in T-deficient but not T cell-intact hosts, pointing to a role of immune surveillance in preventing emergence of these B cell malignancies. These ATM-deficient lymphomas show considerable chromosomal instability with a recurrent amplification of a 4.48Mb region on chromosome 18 (MMU18), orthologous to a region amplified in some cases of human ABC-DLBCL, and containing Malt1 in the region of highest amplification. Importantly, these lymphomas also depend on NF-kB, MALT1, and BCR signaling for survival. Gene expression analysis revealed strong similarities between these mouse lymphomas and human ABC-DLBCL. This study reveals that ATM is required to prevent the development of B cell lymphomas that model human ABC-DLBCL and identifies an unappreciated role of T cells in preventing the emergence of these tumors.